ANATOMY OF THE SKIN

Maged N. Kamel, M.D.

Cutaneous Sensory System

Keratin

Functions of the Skin

Cutaneous Vascular System

Epidermopoiesis

Nails

Hair

Pigmentary System

Ultrastructure of the Dermo-Epidermal Junction

Sweat Glands

Sebaceous Glands

References

Cutaneous Sensory System

1: Sensory Apparatus of the Skin 2: Connection to the CNS 3: Physiology of Sensory Receptors

Sensory Apparatus of the Skin

The skin is innervated with around one million afferent nerve fibers. Most terminate in the face and extremities; relatively few supply the back. The cutaneous nerves contain axons with cell bodies in the dorsal root ganglia. Their diameters range from 0.2-20 m. The main nerve trunks entering the subdermal fatty tissue each divide into smaller bundles. Groups of myelinated fibers fan out in a horizontal plane to form a branching network from which fibers ascend, usually accompanying blood vessels, to form a mesh of interlacing nerves in the superficial dermis. Throughout their course, the axons are enveloped in Schwann cells and as they run peripherally, an increasing number lack myelin sheaths. Most end in the dermis; some penetrate the basement membrane, but do not travel far into the epidermis.

Sensory endings are of two main kinds: corpuscular, which embrace non-nervous elements, and 'free', which do not. Corpuscular endings can, in turn, be subdivided into encapsulated receptors, of which a range occurs in the dermis, and non-encapsulated, exemplified by Merkel's 'touch spot' which is epidermal.

Each Merkel's touch spot is composed of a battery of Merkel cells borne on branches of a myelinated axon. A Merkel cell has a lobulated nucleus and characteristic granules; it is embedded in the basal layer of epidermal cells, with which it has desmosomal connections; it contains intermediate filaments composed of low molecular weight keratin rather than neurofilament protein.

The Pacinian corpuscle is one of the encapsulated receptors. It is an ovoid structure about 1mm in length, which is lamellated in cross-section like an onion, and is innervated by a myelinated sensory axon which loses its sheath as it traverses the core. The Golgi-Mazzoni corpuscle found in the subcutaneous tissue of the human finger is similarly laminate but of much simpler organization. These last two lamellated end organs are movement and vibration detectors.

The Krause end bulb is an encapsulated swelling on myelinated fibers situated in the superficial layers of the dermis. Meissner corpuscles are characteristics of the papillary ridges of glabrous (hairless skin) skin; they are touch receptors; they have a thick lamellated capsule, 20-40 m in diameter and up to 150 m long. Ruffini endings in the human digits have several expanded endings branching from a single myelinated afferent fibre; the endings are directly related to collagen fibrils; they are stretch receptors.

'Free nerve endings', which appear to be derived from non-myelinated fibers occur in the superficial dermis and in the overlying epidermis; they are receptors for pain, touch, pressure and temperature. Hair follicles have fine nerve filaments running parallel to and encircling the follicles; each group of axons is surrounded by Schwann cells; they mediate touch sensation.



Cutaneous Sensory System: Connection to the CNS

The brain receives two types of sensations: (1) superficial sensations, including pain, temperature and crude touch, and (2) deep sensations, including sense of position, sense of movement, vibration sense, muscle sense and fine touch. Some superficial and deep sensations must reach the cortex to be felt. These are: (1) tactile localization, tactile discrimination and stereognosis, (2) mid-zones of temperarure (between very hot and very cold values), and (3) sense of position and movement.

Pathway of pain, temperature and crude touch sensations: (1) The first order neuron is present in the posterior root ganglion. Its dendrite passes to the periphery to act as a pain receptor, while its axon passes towards the spinal cord. In the spinal cord, it ascends for one or few segments at the tip of the posterior horn forming the Lissauer's tract, and then ends around the cells of the substantia gelatinosa of Rolandi which are present at the tip of the posterior horn of the grey matter. (2) The second order neuron is present in the substantia gelatinosa of Rolandi. Its axon crosses to the opposite side in the anterior commissure near the central canal, then ascends in the lateral spinothalamic tract (ventral spinothalamic tract, in case of crude touch) to terminate in the thalamus. (3) The third order neuron is present in the thalamus. Its axon travels in the posterior limb of the internal capsule behind the pyramidal fibers and terminates in the sensory area of the cerebral cortex (areas 1, 2, and 3).

Pathway of deep sensations and fine touch: (1) The first order neuron is also present in the posterior root ganglion. Its dendrite passes to the periphery, while its axon enters the spinal cord and ascends directly (without relay) in the posterior column of the spinal cord, forming the Gracile and Cuneate tracts. The two tracts end in the medulla around the Gracile and Cuneate nuclei. (2) The second order neuron is present in the Gracil and Cuneate nuclei of the medulla. Its axon crosses to the opposite side then ascends in the brain stem (forming the medial lemniscus) to reach the thalamus where it terminates. (3) The third order neuron is present in the thalamus. Its axon passes upwards in the internal capsule to end in the sensory area of the cerebral cortex.

Physiology of Sensory Receptors 

Adaptation: When a maintained stimulus of constant strength is applied to a receptor, the frequency of the action potentials in its sensory nerve declines over time. There are two types of receptors: (1) tonic slowly-adapting receptors: as the nociceptors (pain receptors) which continue to transmit impulses to the brain as long as the stimulus is applied, thus keeping the CNS continuously informed about the state of the body; and (2) phasic rapidly-adapting receptors: as Pacinian corpuscles--these receptors adapt rapidly and cannot be used to transmit a continuous signal to the CNS -they are stimulated only when the stimulus strength is changed.

Touch sensation is provoked by a harmless stimulus to the skin allowing us to distinguish between hard and soft objects; touch receptors belong to the class of mechanoreceptors and many of them can be found around hair follicles, so removal of hair decreases touch sensitivity; the tips of the fingers and lips are rich in touch receptors.

Tickle and itch: These sensations are experienced when mild stimulation of the pain nerve endings occurs; there are also specific free nerve endings for itch sensation; tickle and itch sensations are transmitted by group C unmyelinated nerve fibers; histamine produces itch while pain signals suppress it; tickle is itch produced by light external moving stimuli and is a pleasurable sensation; itch is an annoying sensation while pain is unpleasant; itch sensation excites the scratch reflex.

Endorphins and enkephalins are important opioid neurotransmitters in the CNS that mediate the sensation of itch. Although morphine alleviates pain, it aggravates itch, as itch and pain share common neurological pathways. The central elicitation of itch by morphine results from binding to opioid receptors and this binding may mimic normal physiological binding of endorphins and enkephakins at these receptor sites. Naloxone, an opioid antagonist, has been found to reduce histamine-provoked itch.

The heparin-containing tissue cells called mast cells have a high histamine content in their granules. They also contain serotonin. Mast cells are particularly numerous in the skin (about 7,000 mast cells per cubic millimeter in normal skin in the subpapillary dermis). Mast cells play an important role in type I immediate hypersensitivity reation (IgE-mediated anaphylactic reaction). n ,

Temperature sensation: Receptors for warmth and cold are specialized free nerve endings; a rise in skin temperature above body temperature causes a sensation of warmth, while a fall in skin temperature below body temperature is experienced as cold sensation; pain is felt if skin temperature increases above 45 C or decreases below 10 C; the mucous membrane of the mouth is less sensitive than the skin, thus tea can be drunk at a temperature which is painful to fingers.

Paradoxical cold: Cold receptors are stimulated by intrinsic heat (e.g., shivering that occurs with fever).

Pain is evoked by non-specific stimuli (chemical, mechanical, thermal, or electrical) of an intensity which can produce tissue damage. Pain is a high threshold sensation. The nociceptors (pain receptors) are free nerve endings. Cutaneous pain may be sharp and localized, or dull and diffuse. A painful stimulus causes at first sharp pain, followed by dull aching pain. Reflex withdrawal movements also occur, with an increase in heart rate and blood pressure. Fast sharp (pricking) pain is mediated by nociceptors innervated by group A delta thick myelinated nerve fibers which transmit pain impulses at a velocity of 20 meter/second. Slow chronic (dull-aching or burning) pain is mediated by nociceptors innervated by group C thin unmyelinated nerve fibers that conduct pain at a low velocity of 1 meter/second.

Algogenic substances: These are pain-producing substances either exogenous (as acids and alkalies), or endogenous (as prostaglandins, bradykinin, ATP, 5-HT [serotonin], and histamine).
Types of Hyperalgesia: (1) Primary hyperalgesia: Hypersensitivity of pain receptors (lowered pain threshold, so that touch can produce pain). It is due to release of algogenic substances (as histamine and prostaglandins) in an inflamed area of the skin (e.g., sunburn). (2) Secondary hyperalgesia: It is not due to a skin lesion. The cause is a CNS lesion (e.g., thalamic syndrome [see: Cutaneous Sensory System: Connection to CNS] and herpes zoster) with facilitation of sensory transmission. The pain threshold in secondary hyperalgesia is normal or elevated, but the pain produced is unpleasant, prolonged and severe.

Cutaneous Vascular System

Circulation through the skin serves two functions: (1) nutrition of the skin tissue, and (2) regulation of body temperature by conducting heat from the internal structures of the body to the skin, where it is lost by exchange with the external environment (by convection, conduction and radiation). (See Also: Sweat Glands.)

The cutaneous circulatory apparatus is well-suited to its functions. It comprises two types of vessels: (1) the usual nutritive vessels (arteries, capillaries and veins), and (2) vascular structures concerned with heat regulation. The latter include an extensive subcutaneous venous plexus which can hold large quantities of blood (to heat the surface of the skin), and arteriovenous anastomoses which are large direct vascular communications between arterial and venous plexuses. Arteriovenous anastomoses are only present in some skin areas which are often exposed to maximal cooling, as the volar surfaces of hands and feet, the lips, the nose and the ear.

The specialized vascular structures just mentioned, bear strong muscular coats innervated by sympathetic adrenergic vasoconstrictor nerve fibers. When constricted, blood flow into the subcutaneous venous plexus is reduced to almost nothing (minimal heat loss); while, when dilated, extremely rapid flow of warm blood into the venous plexus is allowed (maximal heat loss).

The blood flow required for the nutrition of the skin is very small (about 40ml/min). Yet, at ordinary skin temperature, the amount of blood flowing through the skin is 10 times (=0.25L/m2 =400ml/min in a normal adult) more than what is needed for the nutrition of the tissues.

The rate of cutaneous blood flow required to regulate body temperature varies in response to changes in the metabolic activity of the body and/or the temperature of the surroundings. Exposure to extreme cold reduces the rate of blood flow to very low values, so that the nutritive function may sometimes suffer. On the other hand, heating the skin until maximal vasodilatation occurs (as in hot climate), increases the cutaneous blood flow 7 times the normal value (2.8L/min.). This diminishes the peripheral resistance and increases the cardiac output, which may lead to the decompensation of the heart in borderline-heart-failure subjects exposed to hot weather.

Located in the anterior hypothalamus is a small center that controls body temperature. Heating this area causes vasodilatation of all the skin vessels of the body and sweating. On the contrary, cooling this center causes vasoconstriction of skin vessels and stoppage of sweat secretion. The hypothalamus exerts its controlling effect on the skin vessels through sympathetic nerves. There are also vasoconstrictor reflex centers in the spinal cord.

Sympathetic noradrenergic vasoconstrictor fibers supply the vessels of the skin throughout the body. This constrictor system is extremely powerful in the feet, hands, lips, nose and ears (areas where large numbers of arteriovenous anastomoses are found). At normal body temperature, the sympathetic vasoconstrictor nerves keep these anastomoses closed. However, when the body becomes overheated, the sympathetic discharge is greatly reduced so that the anastomoses dilate allowing large quantities of warm blood to flow into the subcutaneous venous plexus, thereby promoting heat loss from the body.

Active vasodilatation of the blood vessels of the skin of forearms and trunk may be due to the discharge of sympathetic cholinergic vasodilator fibers supplying these areas. The increased activity of sweat glands in hot weather may also contribute to the vasodilatation by releasing kallikrein, an enzyme which splits the polypeptide bradykinin from a globulin present in the interstitial spaces. Bradykinin is a powerful vasodilator.

In cold weather, when the temperature reaches 15 C, we get maximal vasoconstriction of skin blood vessels. However, in a normal subject, if the skin temperature is lowered below 15 C, the cutaneous vessels begin to dilate. This dilatation is attributed to the direct local effect of cold causing paralysis of the contractile musculosa of skin blood vessels and blocking nerve impulses to the vessels. Maximal vasodilatation occurs at 0 C, increasing the blood flow through the skin which prevents freezing of the exposed areas of the body.

The cutaneous circulation also serves as a blood reservoir. Under conditions of circulatory stress, e.g., exercise and hemorrhage, sympathetic stimulation of subcutaneous venous plexus forces a large volume of blood (5-10% of the blood volume) into the general circulation.

Reactive hyperaemia occurs if one, for example, sits on one portion of his skin for 30 minutes or more then removes the pressure. In such conditions, the individual will notice intense redness of the skin at the site of previous pressure, which resulted from accumulation of vasodilator metabolites at that site (due to decreased availability of nutrients to the tissues during compression).

The triple response: A firm stroke applied to the skin results in three local reactions collectively known as the triple response: (a) at first blanching of the skin occurs for a very brief moment (due to pressure exerted by the stroke), followed by a red line due to capillary dilatation (caused by histamine and other mediators of vasodilatation released from damaged tissues); (b) a red flare follows the red line by 20-40 seconds and is due to arteriolar dilatation through a local axon reflex (the axon reflex is caused by stimulation of the pain nerve fibers with impulses passing up these fibers and down to their endings where vasodilator algogenic--i.e, pain-inducing--substances are released); (c) finally, a wheal may appear after 1 minute, reaching full development within 5 minutes (the wheal is best seen in people with hypersensitive skin; it is due to release of histamine which causes arteriolar dilatation and venular constriction, raising the capillary blood pressure with transudation of fluid into the tissues).

Epidermopoiesis: Introduction

The epidermis is a multilayered structure (stratified epithelium) which renews itself continuously by cell division in its deepest layer, the basal layer. The principal cell type, the epidermal cell, is most commonly referred to as a keratinocyte. The cells produced by cell division in the basal layer constitute the prickle cell layer and as they ascend towards the surface they undergo a process known as keratinization which involves the synthesis of the fibrous protein keratin. The total epidermal renewal time is 52-75 days. The cells on the surface of the skin, forming the horny layer (stratum corneum), are fully keratinized dead cells which are gradually abraded by day to day wear and tear from the environment.

The basal layer is composed of columnar cells which are anchored to a basement membrane--this lies between the epidermis and dermis. The basement membrane is a multilayered structure from which anchoring fibrils extend into the superficial dermis. Interspersed amongst the basal cells are melanocytes, large dendritic cells responsible for melanin pigment production.

The prickle cell layer acquires its name from the spiky appearance produced by intercellular bridges (desmosomes) which connect adjacent cells. Scattered throughout the prickle cell layer are numbers of dendritic cells called Langerhans cells. Like macrophages, Langerhans cells originate in the bone marrow and have an antigen-presenting capacity.

Above the prickle cell layer is the granular layer which is composed of rather flattened cells containing numerous darkly-staining particles known as keratohyaline granules. Also present in the cytoplasm of cells in the granular layer are organelles known as lamellar granules (Odland bodies). Lamellar granules contain lipids and enzymes, and they discharge their contents into the intercellular spaces between the cells of the granular layer and stratum corneum, providing something akin to 'mortar' between the cellular 'bricks.' In the granular layer the cell membranes become thickened as a result of deposition of dense material on their inner surfaces.

The cells of the stratum corneum are flattened keratinized cells which are devoid of nuclei and cytoplasmic organelles. These cellular components degenerate in the upper granular layer. Adjacent cells overlap at their margins and this locking together of cells, together with intercellular lipid, forms a very effective barrier. The stratum corneum varies in thickness depending on the region of the body, being thickest over the palms of the hands and soles of the feet.

The rate of cell production in the germinative compartment of the epidermis must be balanced by the rate of cell loss at the surface of the stratum corneum. The control mechanism of epidermopoiesis consists of a balance of stimulatory and inhibitory signals. Wound healing provides a model to examine the changes in growth control that occur in establishing a new epidermis. Wounding of the skin is followed by a wave of epidermal mitotic activity, which represents the effects of diffusible factors spreading from the wound into the surrounding tissue. These factors include cytokines and growth factors. There production is not limited to immune cells as they are produced by keratinocytes in vitro and can be found in physiological amounts in normal human skin.

Regulation of Epidermopoiesis: Stimulatory Factors

The growth factors which stimulate the epidermal cells include: epidermal growth factor (EGF), transforming-growth-factor-alpha (TGFalpha), interleukins (IL) and other immunological cytokines, and basic fibroblast growth factor (bFGF).

EGF binds to specific cell-surface receptors (EGFR, a trans-membrane glycoprotein receptor) present in the basal layer of the human epidermis. Following binding of EGF to EGFR, the receptor is internalized and carries EGF into an intracellular cycle within the cytoplasm and the nucleus to mediate all its effects. EGF has been shown to increase the growth and persistence of epidermal keratinocytes and to promote wound healing in vitro. EGF transcripts are not found in the epidermis, but in salivary glands and intestinal tract.

TGFalpha was the first growth factor known to be produced by keratinocytes. Its mRNA predominates in the basal compartment of the epidermis. TGFalpha is related to EGF. It binds to and activates the EGF receptor. It stimulates keratinocyte growth.

The normal epidermis also contains large amounts of Interleukin-1. There are two forms, alpha and beta, and unlike macrophages, the epidermis largely produces IL-1alpha. IL-1 has been shown to be mitogenic for keratinocytes (other effects include: fibroblast proliferation and synthesis of collagenase, stimulation of IL-2 production, stimulation of B-cell function, and fever induction). IL-1 releases IL-6 from keratinocytes. IL-6 appears to stimulate growth of keratinocytes and can be detected in epidermal cells. Keratinocytes also synthesize IL-3, IL-4, IL-8 (neutrophil activating protein), and granulocyte-macrophage colony stimulating factor.

Thus the epidermal keratinocytes can, under activation conditions, secrete a large number of cytokines, which can modulate lymphocyte activation and granulocyte function. These factors do not work in isolation but have complex interactions, and may be synergistic or antagonistic. The factors controlling synthesis and secretion of these factors may be important in the pathogenesis of skin disease as well as epidermal growth control.

The regulation of the effects of growth factors includes the control of expression of the specific growth-factor receptors. The epidermal cell cycle is also controlled by the intracellular concentrations of the cyclic nucleotides: cAMP and cGMP. These are small molecules which are formed and broken down intracellularly as a response to external signals acting on the cell membrane. Cyclic AMP is believed to be the intracellular agent or '2nd messenger' of those hormones, i.e. catecholamines and polypeptides, which do not themselves penetrate the surface of cells. Cyclic AMP inhibits epidermal cell division while cGMP stimulates it. Epidermal mitosis exhibits a circadian rhythm, which is inversely related to blood adrenaline levels.

Steroid hormones like testosterone enter the target cells. Epidermal keratinocytes contain 5 alpha-reductase enzyme and they can convert testosterone to 5 alpha-dihydrotestosterone (DHT). DHT binds to specific cytosol receptors which then translocate to the nucleus, thereafter, altering protein synthesis via messenger RNA. Androgens and vitamin A stimulate epidermal mitosis, while glucocorticoid hormones inhibit it.

Prostaglandins, which are metabolic products of arachidonic acid, can affect nucleotide metabolism. Prostaglandins of the D and E series can increase cAMP, although not all such components are present in the epidermis. The main prostaglandin formed in the epidermis is PGE2. On the other hand, lipoxygenase products of arachidonic acid metabolism namely HETE (12-Hydroxy-Eicosa-Tetra-Enoic acid) and the leucotrienes are capable of inducing epidermal cell proliferation in vitro.

Polyamines, including spermidine, putrescein and spermine, stimulate mitosis. Ornithine decarboxylase is a particularly important enzyme for the generation of this group of substances.

Regulation of Epidermopoiesis: Inhibitory Factors

Growth inhibitors for keratinocytes include chalones, transforming-growth-factor-beta (TGFbeta), alpha and gamma interferons (IFN-gamma), and tumour necrosis factor (TNF).

Chalones are polypeptides produced by suprabasal cells which slow basal mitosis. TGFbeta stimulates fibroblast growth and increases fibrosis but inhibits the growth of keratinocytes. Thus although it may have an inhibitory effect on epidermal growth the effect on wound healing is complex, because of mesenchymal effects (on fibroblasts) and it has been reported to stimulate wound healing.

Alpha and gamma interferons have cytostatic effects on keratinocytes both in vivo following systemic administration and in vitro. Following stimulation with IFN-gamma, keratinocytes express class II antigens, predominantly HLA-DR. High doses of Interferon-gamma are cytotoxic.

Thirty percent of administered TNF localizes in epidermis suggesting the presence of many TNF-binding sites. Keratinocytes also secrete TNF. TNF can cause release of IL-1. It stimulates fibroblast proliferation and cytokine production. TNF has also been shown to be reversibly cytostatic to keratinocytes.

Functions of the Skin

The skin is structured to prevent loss of essential body fluids, and to protect the body against the entry of toxic environmental chemicals. In the absence of a stratum corneum we would all lose significant amounts of water to the environment, and rapidly become dehydrated. The stratum corneum with its overlapping cells and intercellular lipid, makes diffusion of water into the environment very difficult.

The skin is also part of the innate immunity (natural resistance) of the body against invasion by micro-organisms. The dryness and constant desquamation of the skin, the normal flora of the skin, the fatty acids of sebum and lactic acid of sweat, all represent natural defense mechanisms against invasion by micro-organisms. Langerhans cells present in the epidermis have an antigen-presenting capacity and might play an important role in delayed hypersensitivity reactions. They also play a role in immunosurveillance against viral infections. Langerhans cells interact with neighboring keratinocytes, which secrete a number of immunoregulating cytokines, and epidermotropic T-cells forming the skin immune system: SALT (skin associated lymphoid tissue).

Melanin pigment of the skin protects the nuclear structures against damage from ultraviolet radiation.

The skin is also a huge sensory receptor for heat, cold, pain, touch, and tickle. Parts of the skin are considered as erogenous zones. The skin has great psychological importance at all ages. It is an organ of emotional expression and a site for the discharge of anxiety. Caressing favors emotional development, learning and growth of newborn infants.

The skin is a vital part of the body's temperature regulation system, protecting us against hypothermia and hyperthermia, both of them may be fatal (specialized vascular structures of the dermis/insulation by fat in subcutaneous tissue/evaporation of sweat).

The skin plays an important role in calcium homeostasis by contributing to the body's supply of vitamin D. Vitamin D3 (cholecalciferol) is produced in the skin by the action of ultraviolet light on dehydrocholesterol. It is then hydroxylated in the liver and kidneys (needs parathyroid hormone to activate alpha-hydroxylase) to 1,25 dihydroxycholecalciferol, the active form of vitamin D. This anti-rachitic vitamin acts on the intestine increasing calcium absorption (through stimulation of synthesis of calcium-binding proteins in the mucosal cells of the intestine), as well as on the kidneys promoting calcium reabsorption.

Fingerprints, the characteristic elevated ridge patterns on the finger tips of humans, are unique to each individual. The fingers and toes, the palms of the hands and soles of the feet, are covered with a system of ridges which form certain patterns. The term dermatoglyphics is applied to both the configurations of the ridges, and also to the study of fingerprints. The medicolegal importance of the ridge patterns of fingerprints, characteristic dermatoglyphic abnormalities frequently accompany many chromosomal aberrations.

Hair

Hair performs no vital function in humans, whose body could be perpetually depilated without any physiological disadvantages. At the same time the psychological functions are inestimable: scalp hair is a major social and sexual display feature of the human body.

Hairs grow out of tubular invaginations of the epidermis known as follicles, and a hair follicle and its associated sebaceous glands are referred to as a pilosebaceous unit. Hair follicles extend into the dermis at an angle. A small bundle of smooth muscle fibers, the arrector pili muscle, extends from just beneath the epidermis and is attached to the side of the follicle at an angle. Arrector pili muscles are supplied by adrenergic nerves, and are responsible for the erection of hair during cold or emotional stress ('goose flesh'). The sebaceous gland is attached to the follicle just above the point of attachment of the arrector pili.

At the lower end of the follicle is the hair bulb, part of which, the hair matrix, is a zone of rapidly dividing cells which is responsible for the formation of the hair shaft. Hair pigment is produced by melanocytes in the hair bulb. Cells produced in the hair bulb become densely packed, elongated and arranged parallel to the long axis of the hair shaft. They gradually become keratinized as they ascend in the hair follicle.

The main part of each hair fibre is the cortex, which is composed of keratinized spindle-shaped cells. Terminal hair (as that of scalp) have a central core known as the medulla consisting of specialized cells which contain air spaces (see: Types of Hair). Covering the cortex is the cuticle, a thin layer of cells which overlap like the tiles on a roof, with the free margins of the cells pointing towards the tip of the hair.

The cross-sectional shape of hair varies with body site and with race. African hair is distinctly oval in cross-section, and pubic, beard and eyelash hairs are oval in all racial types. The form of scalp hair also differs among human races (e.g., the peppercorn pattern in black Africans).

The average rate of growth of human scalp hair is 0.37mm per day. In women scalp hair grows faster and body hair grows more slowly than in men. The rate of growth of body hair is undoubtedly increased by androgens, since it can be reduced by treatment with antiandrogenic steroids.

Hair: Types and Growth Cycle

The first hair to be produced by the fetal follicles, so called lanugo, is fine, soft, unmedullated, and usually unpigmented. Lanugo is normally shed in utero in the seventh or eighth month of gestation.

Postnatal hair can be divided into vellus, which is soft unmedullated, usually unpigmented, and seldom more than 2cm long, and terminal hair, which is longer, coarser, and often medullated and pigmented. There is, however, a range of intermediate types.

The type of hair produced by any particular follicle can change. The most striking example is the replacement of vellus by terminal hair at puberty which starts in the pubic regions. This leads us to the definition of androgen-dependent hair. It is obvious from the events of puberty that pubic, axillary, facial, and body hair are hormone-dependent. So, paradoxically, is pattern baldness (male), in which terminal hair is replaced by fine, short hair resembling vellus. The growth of male beard depends on testicular hormones. The action of testosterone in general involves its reduction to 5 alpha-dihydrotestosterone and binding to an intracellular receptor.

The most important feature of hair follicles is that their activity is intermittent (cyclical). As the hair reaches a definitive length, it is shed to be replaced by a new hair. Thus a hair follicle will pass into three stages: an active (anagen) stage, a resting (catagen) stage, and a telogen stage where the hair stops growing to be finally shed. In human scalp hair, the anagen stage takes about three years, the catagen stage takes three weeks, and the telogen phase takes three months. The hair cycle occurs in different hair follicles asynchronously, i.e., at a given time, each individual hair follicle is at a different stage of the hair cycle.

Keratin

Electron microscopical examination of cells from all tissues reveals that they contain a complex, heterogenous, intracytoplasmic system of filaments. The components of this system include actin, myosin, and tubulin, whose diameters average approximately 60A, 150A, and 250A, respectively. In addition, other intracytoplasmic filaments were noted, and since the diameter of these latter structures was found to be between 70 and 100A, they were called intermediate filaments.

Intermediate filaments form a major part of the cytoskeleton of most cells and fulfill a variety of roles related to cell shape, spatial organization, and perhaps informational transfer. The nucleus contains structures related to these intermediate filaments and many intracellular components including polyribosomes, mitochondria, nucleic acids, enzymes, and cyclic nucleotides are attached to the cytoskeleton.

Based on their biochemical, biophysical, and antigenic properties, a number of classes of intermediate filaments can be recognized in different cell types: desmin (skeletin) in muscle cells, glial fibrillary acidic filaments in glial cells, neurofilaments in neurons, vimentin in mesenchymal cells, and keratin in epithelial cells. In cultured epidermal cells, keratins account for up to 30% of the cellular protein, while in stratum corneum, keratin accounts for up to 85% of the cellular protein.

At least 19 keratin proteins can be identified ranging in molecular weight from approximately 40,000 to 68,000 micrograms. Moll and his coworkers published their human keratin catalogue in 1982. According to this catalogue, there are two keratin subfamilies. The molecular weight of the members of one (the basic subfamily) is relatively larger than that of the members of the other (the acidic subfamily). Each of the keratins is the product of a unique gene and, in essentially all situations, the keratins are expressed as pairs containing one member of each subfamily. The two members of each pair are in the same size rank order within their respective family, e.g., the largest acidic keratin is expressed with the largest basic.

The type of keratin differs in different tissues, i.e, there are different types of keratin for keratinized epidermis, hyperproliferative epidermis of palms and soles, corneal epithelium, stratified epithelium of the esophagus and cervix, and simple epithelium of the epidermal glands. As mentioned before, keratin is the main structural protein of the epidermis.

The keratinocytes in the basal layer and prickle cell layer synthesize keratin filaments (tonofilaments) which aggregate into bundles (tonofibrils). Eventually, in the cells of the stratum corneum, these bundles of keratin filaments form a complex intracellular network embedded in an amorphous protein matrix. The matrix is derived from the keratohyaline granules of the granular layer. Epidermal keratinization results in the production of a barrier which is relatively impermeable to substances passing in or out of the body.

Nails

The nail acts as a protective covering to the end of the digit and assists in grasping small objects. The nail has also a cosmetic function. The major part of this appendage is the hard nail plate, which arises from the matrix (see below). The nail plate is roughly rectangular and flat in shape but shows considerable variation in different persons. The pink color of the nail bed results from its extensive vascular network and can be seen because of the transparency of the plate.

Usually in the thumbs, uncommonly in other fingers and in the large toenails, a whitish crescent-shaped lunula is seen projecting from under the proximal nail folds. The lunula is the most distal portion of the matrix and determines the shape of the free edge of the nail plate. Its color is due in part to the effect of light scattered by the nucleated cells of the matrix and in part to the thick layer of epithelial cells making up the matrix.

As the nail plate emerges from the matrix, its lateral and proximal borders are enveloped by folds of the skin termed the lateral and proximal nail folds. The skin underlying the free end of the nail is referred to as the hyponychium and is contiguous with the skin on the tip of the finger.

The nail plate is formed by a process which involves flattening of the basal cells of the matrix, fragmentation of the nuclei, and condensation of cytoplasm to form horny flat cells which are strongly adherent to one another.

Fingernails grow faster than toenails. Nails of individual fingers of the same hand grow at different rates. There are also familial tendencies favouring similar growth rates among persons and it has been noted that nail growth is increased during summer and diminished in cold climates.

Many systemic disorders may produce a decrease in the rate of nail growth or thinning and grooving of the plate. This phenomenon is best appreciated weeks after the event has occured. Acute viral infectious diseases as mumps and measles, starvation, and some types of anaemia are among the causes. Increase in the growth rate can be seen during pregnancy, nail biting, trauma and during regrowth after avulsion.

Pigmentary System

Melanocytes and Skin Color

The melanin pigmentary system is composed of functional units called epidermal melanin units. Each unit consists of a melanocyte that supplies melanin pigment to a group of keratinocytes (about 36). Pigmentation is determined primarily by the amount of melanin transferred to the keratinocytes.

The melanocyte is a dendritic cell present in the basal layer of the epidermis with no desmosomes (intercellular bridges) or tonofilaments. In H & E-stained sections, it has a small dark nucleus and a clear cytoplasm. It can be stained black with Fontana Masson (Silver) stain as it contains melanin, and more specifically with DOPA reaction as it has the ability to form melanin (tyrosinase-containing cell).

Melanocytes arise from the neural crest as melanoblasts and migrate to the dermis, hair follicles, leptomeninges, uveal tract and retina. By the 8th week of intrauterine life, they start to migrate from the dermis to the epidermis. Although full melanocyte migration is normally completed prior to birth, residual dermal melanocytes are sometimes left (clinically appearing as mongoloid spots in the sacral area of oriental and black infants).

Melanosomes are membrane-bound organelles located in the cytoplasm of melanocytes and bearing tyrosinase enzyme. They are responsible for melanin synthesis and pigment transfer from the melanocyte to the surrounding keratinocytes. During their passage from the perinuclear area of the melanocyte to the dendrites, the melanosomes show four stages of development: I and II (with no melanin deposition), III (with high levels of tyrosinase activity and is partially obscured by melanin deposition), and IV (with low levels of tyrosinase activity and is completely obscured by melanin deposition). Pigment transfer occurs by keratinocyte phagocytosis of melanosome-containing dendritic tips. As squamous cells differentiate, the melanosomes within them are degraded by lysosomal enzymes.

The differences in racial pigmentation are not due to differences in the number of melanocytes, but rather to differences in melanocyte activity. In black skin, there is greater production of melanosomes, higher degree of melanization of melanosomes, and larger unaggregated melanosomes showing slow rate of degradation.

Melanin: Types, Synthesis and Hormonal Regulation

Melanin is a brown-black, light-absorbing pigment, protecting the skin against ultraviolet rays. Two major forms of melanin exist in humans: (1) Eumelanin, a brown to black pigment synthesized from Indole 5,6-quinone and found within the ellipsoid melanosomes; and (2) Phaeomelanin, a yellow-red pigment found within the spherical melanosomes.

Tyrosinase is synthesized by the ribosomes of the rough endoplasmic reticulum (rER) and transported through the smooth endoplasmic reticulum (sER) to the Golgi apparatus. It is then released within membrane-bound vesicles. Meanwhile, structural melanosomal proteins are also synthesized on the rER and are then incorporated into vesicles at the sER. Fusion of the two types of vesicles (tyrosinase and structural melanosomal proteins) results in the formation of a melanosome. As the melanosome matures and more melanin is deposited on its lamellar matrix, it passes into the dendrite of the melanocyte.



There are receptors on the surface of melanocytes for melanocyte-stimulating hormone (MSH). MSH, ACTH (similar to MSH in the arrangement of first 13 amino acids), estrogen and progesterone, all stimulate pigmentation through increasing cAMP and tyrosinase activity, resulting in increased melanin formation and transfer.

Sebaceous Glands

Sebaceous glands are found on all areas of the skin with the exception of the palms, soles, and dorsa of the feet. They are holocrine glands, i.e., their secretion is formed by complete destruction of the cells.

Most sebaceous glands have their ducts opening into hair follicles (pilosebaceous apparatus). Free sebaceous glands (not associated with hair follicles) open directly to the surface of the skin, e.g., Meibomian glands of the eyelids, Tyson's glands of the prepuce, and free glands in the female genitalia and in the areola of nipples.

The production of sebum is under hormonal control and sebaceous secretion is a continuous process. Sebaceous gland development is an early event in puberty, and the prime hormonal stimulus for this glandular development is androgen. Although the sebaceous glands are very small throughout the prepubertal period, they are large at the time of birth, probably as a result of androgen stimulation in utero, and acne may be seen in the neonatal period. It should be noted that: (1) sebum production is low in children; (2) in adults, sebum production is higher in men than in women; (3) in men, sebum production falls only slightly with advancing age, whereas in women it decreases significantly after the age of 50. Orchidectomy causes a marked decrease in sebum production. Therefore, it can be assumed that testicular androgen maintains sebum production at high levels in men. The role of adrenal androgens is also important, specially in women where they play a contributory role in sebum production together with the ovaries.

Estrogens have a profound effect on sebaceous gland function which is opposite of that of androgens. In both sexes, estrogen administration decreases the size of the sebaceous glands and the production of sebum.

The sebum is composed of triglycerides and free fatty acids, wax esters, squalene, and cholesterol. The sebum controls moisture loss from the epidermis. The water-holding power of cornified epithelium depends on the presence of lipids. The sebum also protects against fungal and bacterial infections of the skin due to its contents of free fatty acids. Ringworm of scalp becomes rare after puberty.

Sweat Glands

Generalized sweating is the normal response to exercise or thermal stress by which human beings control their body temperature through evaporative heat loss. Failure of this mechanism can cause hyperthermia and death. (See Also: Cutaneous Vascular System.)

Humans have several million eccrine sweat glands distributed over nearly the entire body surface (except labia minora and glans penis). The total mass of eccrine sweat glands roughly equals that of one kidney, i.e., 100g. A person can perspire as much as several litres per hour and 10 litres per day, which is far greater than the secretory rates of other exocrine glands such as the salivary and lacrimal glands and the pancreas.

Each eccrine sweat gland consists of a secretory coil deep in the dermis, and a duct which conveys the secreted sweat to the surface. The secretory activity of the human eccrine sweat glands consists of two major functions: (1) secretion of an ultrafiltrate of a plasmalike precursor fluid by the secretory coil in response to acetylcholine released from the sympathetic nerve endings, and (2) reabsorption of sodium in excess of water by the duct, therby producing a hypotonic skin surface sweat. Under extreme conditions where the amount of perspiration reaches several litres a day, the ductal reabsorptive function assumes a vital role in maintaining homeostasis of the entire body.

In addition to the secretion of water and electrolytes, the sweat glands serve as excretory organ for heavy metals, organic compounds, and macromolecules. The sweat is composed of 99% water, electrolytes, lactate (provides an acidic pH to resist infection), urea, ammonia, proteolytic enzymes, and other substances.

There is a hypothalamic preoptic sweat center that plays an essential role in regulation of body temperature. Sweat secretion on palms and soles is more or less continuous (perpetual sweating) when humans are awake. In contrast, those glands on the general skin surface respond predominantly to thermal stimuli (thermal sweating). Both types of sweating can be inhibited by atropine as all sweat glands in different areas of the body are stimulated by the same sympathetic cholinergic mechanism. Sweating induced by emotional stress (emotional sweating) can occur over the whole skin surface, but usually it is confined to palms, soles, axillae, and the forehead.

The term apocrine glands was given to sweat glands present in the axillae and anogenital area which are under the control of sex hormones, mainly androgens. But nowadays by electron microscopy, these apocrine glands (apocrine = apical part of the cell is destroyed during the process of secretion) proved to be merocrine in nature (merocrine = no destruction of the cell during the process of secretion). The "apocrine" sweat of humans has been described as milky (because it is mixed with sebum due to shared duct) and viscid, without odour when it is first secreted. Subsequent bacterial action is necessary for odour production. Unlike eccrine glands which have a duct that opens onto the skin surface independently of a hair follicle (atrichial), apocrine glands have a duct that opens into a hair follicle (epitrichial).

Ultrastructure of the Dermo-Epidermal Junction

The most superficial component of the junction is the basal plasma membrane of keratinocytes, melanocytes and Merkel cells.

Hemidesmosomes superficially resemble focal thickening of the basal plasma membrane of keratinocytes. At higher magnification, however, they can be seen to have a complicated ultrastructure which resembles half a desmosome. Hemidesmosomes consist of an intracellular component, the attachment plaque, which is associated with tonofilaments, and an extracellular component, known as the sub-basal dense plate. This latter structure is located in the lamina lucida (see below) and resembles a fine, dense line parallel to and just beneath the plasma membrane. Hemidesmosomes are important in maintaining adhesion between dermis and epidermis.

Immediately beneath the basal plasma membrane is the basement membrane which consists of three layers: the lamina lucida, the lamina densa and the lamina fibroreticularis (sub-lamina densa).

Distributed throughout the lamina lucida are anchoring filaments. Anchoring filaments are very fine structures that are oriented vertically between the lamina densa and basal plasma membrane.

The lamina densa is an electron dense amorphous layer that lies parallel to and below the lamina lucida.

Anchoring fibrils are the major constituent of the fibroreticular layer of the basement membrane. These are short, often curved structures, with an irregular cross-banding, that insert into the lamina densa and extend into the upper part of the dermis. They may also insert into amorphous bodies in the superficial dermis known as anchoring plaques, or curve back to have a second insertion in the lamina densa.

Another component of the lamina fibroreticularis are the elastic microfibril bundles, each consisting of many microfibrils that extend into the dermis and may enmesh with the microfibrillar system of dermal elastic fibers.

Bullous pemphigoid antigen is a glycoprotein synthesized by keratinocytes and recognized by circulating autoantibodies in patients with bullous pemphigoid; it has been localized to hemidesmosomes--mainly intracellularly, but to a lesser degree, also just outside the cells.

Laminin, a high-molecular-weight glycoprotein required for cell adhesion, has been immunolocalized to lamina lucida. Fibronectin has also been immunolocalized to the lamina lucida..

Type IV collagen and KF-1 antigen have been immunolocalized to the lamina densa.

Type VII collagen and Epidermolysis bullosa acquisita (EBA) antigen have been immunolocalized to anchoring fibrils and plaques. Type VII collagen has a role in normal dermo-epidermal adherence. AF1 and AF2 antigens have also been immunolocalized to the anchoring fibrils.

Figure 1: Diagram of the ultrastructure of the dermo-epidermal junction showing the sites of cleavage (blister formation) in the three main types of epidermolysis bullosa, a genetically-determined bullous disorder.



EB, Epidermolysis Bullosa; AD, Autosomal Dominant; AR, Autosomal Recessive; DEJ, Dermo-Epidermal Junction; BP Ag, Bullous Pemphigoid Antigen; LL, Lamina Lucida; LD, Lamina Densa; KF-1, an antigen that has been immunolocalized to the lamina densa; SLD, Sub-Lamina Densa. ((c) 1994 Dr. Maged N. Kamel)

References

Champion RH, Burton JL and Ebling FJG (eds): Textbook of Dermatology (Rook), 5th ed, 4 vol, Blackwell, Oxford, 1992
Fitzpatrick TB, Eisen AZ, Wolff K, Freedberg IM and Austen KF (eds): Dermatology in General Medicine, 3d ed, 2 vol, McGraw-Hill, New York, 1987
Ganong WF: Review of Medical Physiology, 14th ed, Appleton & Lange, Connecticut, 1989
Graham-Brown R and Burns T: Lecture Notes on Dermatology, 6th ed, Blackwell, Oxford, 1990


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